The goals of our Center, Modifiers of FMR1-associated disorders: application of high throughput technologies, are targeted to the RFA research area to Advance the understanding of the pathophysiology of FMR1 Related Conditions. The completion of the proposed aims from the three research projects will lead to the identification of the genetic basis of variable expressivity or incomplete penetrance of FMR1- associated conditions. Project A will focus on the variable expression of epilepsy among boys with Fragile X syndrome (FXS), a co-morbid condition that occurs among 15% of affected boys and we speculate that variation elsewhere in the genome is responsible. Likewise, Project B will focus on the incomplete penetrance of Fragile X tremor/ataxia syndrome (FXTAS) in men, a neurodegenerative disorder among those with the permutation (PM), with a lifetime prevalence of 30% among males. Project C focuses Fragile X association primary ovarian insufficiency (FXPOI), which manifests in 20% of PM carriers as premature ovarian failure (POF), or cessation of menses prior to age 40. POF leads to infertility and estrogen-deficiency related disorders usually reserved for the aged. Our goal is to identify and understand the extent of the epistemic effects of modifying genes on these three Mendelian disorders. The Center will include three projects and two shared cores, all administered by an Administrative Core. Each proposed research project will take the same novel approach to define a set of candidate genes for further study in mammalian systems. They will: 1) use the Recruitment Core B to ascertain the 100 cases and 100 controls drawn from extreme phenotypic tails of each disorder, 2) conduct whole genome sequencing on each of the 100/100 cases/controls series using the expertise and experience of the Genomics and Analytical Core C, and 3) after validating variants, assess the function of prioritized genes using the established phenotypic assays in the corresponding Drosophila models. The research we propose in our Center is highly innovative, using cutting-edge technologies, to answer fundamental questions related to Fragile X-related disorders. All Center investigators are part of Emory University, an institution with possibly the largest group of independent faculty working on Fragile X-related disorders and with nearly a 30-year history of contributions to the field. Moreover, an added synergy and excitement within this Center is driven by the common theme among all the projects, ensuring a highly interactive and productive research environment.